Continued from Psychiatrists and Clinical Depression – Part 1
Psychiatry’s history makes it a contender for being one of the worst of all the medical specialties. Yet some things have changed as methods have been discovered to probe the systemic elements of the body, brain, and mind. Psychiatry, one of the most complex areas of medicine, is finally becoming a more evidence-based science. The following impressive list of accomplishments reveals how far psychiatry and medicine have advanced in search of the systemic elements of the body, brain, and mind.
Genetics and Depression
With the development of genetic mapping, which began in 1911 and became sophisticated in the 1980s with DNA-based molecular maps, genetic research on depression revealed a genetic basis for depression. In an article titled “A Brief History of Psychotherapy,” the authors describe a 1987 study related to one form of depression, Manic-Depression:
In 1987, psychiatrist Janice Egeland and colleagues from Yale and M.I.T. released a groundbreaking study identifying bio-chemical anomalies on the chromosomes of one extended Old-Order Amish family with disproportionately high rates for manic-depressive illness. Egeland and her associates, using molecular gene-mapping technology on blood samples drawn from each of the 81-member clan, found DNA markers on a dominant gene conferring a predisposition to manic-depressive illness in the family. Egeland’s research enlivens psychology’s classic “nature vs. nurture” debate. Her study provides the strongest evidence so far for a link between manic depression and a specific biochemical factor, something in the blood or “siss im blut,” as the Amish say.[i]
Later studies have confirmed a direct link between genetics and depression. These studies primarily focus on an epigenetic model that shows the interaction between genetics and environmental factors.
The risk for major depression is both genetically and environmentally determined…. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant epigenetic mechanisms targeting stress response pathways, neuronal plasticity, and other behaviorally relevant pathways that have been implicated in major depression.[ii]
Over the last forty years, much progress has been made as other systems of the body were found to be related to major depression and other related forms of depression, such as manic-depression and post-partum depression. New technology enabled researchers to learn more about the structure and interrelationships of bodily organs and their systems.
The Development of the MRI
Magnetic Resonance Imaging (MRI), developed in the 1970s, came into clinical use in the mid-1980s. The MRI enabled medical doctors and researchers to take pictures of the inside of the body. Various organs could be examined. Thus, pictures could be made of the brain, its structure and size. These images revealed that the brains of depressed individuals were often different from those of nondepressed individuals. The development of the Functional Magnetic Resonance Imaging (fMRI) in the 1990s enabled medical doctors and researchers to see the brain actually function.
Functional MRI is a type of MRI scan that can show which areas of your brain are most active. Tracking and comparing that activity to what you were doing at the time can help “map” your brain activity…. An fMRI scan uses the same MRI machine, but is special because it tracks blood flow in different parts of your brain. Your brain cells use more oxygen when they’re working. That means following the blood flow shows the areas of your brain that are working hardest. Those areas appear brighter on an fMRI scan.[iii]
Although fMRI is primarily used in brain surgery, researchers also use it to examine people with various brain abnormalities, such as Alzheimer’s, depression, and other mental issues. Through both the MRI and the fMRI, researchers have found that brain size, structure, and function (activity) may vary between clinically depressed and nondepressed individuals.
A 2023 review of research discusses using the MRI and fMRI to study depression and various treatment modalities. The fMRI is used to assess the efficacy of a medication by measuring changes in brain activity. Thus, even though these studies are early in their development, one can see how the brain function is related to the mind and how it is functioning in mental disorders, such as the various forms of depression. One difficulty the researchers had was that depression “is often accompanied by anxiety or trauma-related disorders.”[iv] They propose multiple modalities be used, “from genetics, blood, behavioral data, and a variety of imaging modalities [e.g., magnetoencephalography (MEG), MRI, positron emission tomography (PET)], which could lead to more direct links between disorders and drug effects.”[v]
In their concluding remarks, the authors say:
These findings highlight the considerable promise of fMRI for studying and developing drugs targeted at mental health conditions in general and depression in particular. Nevertheless, a gap persists between the extensive use of fMRI in research and its systematic and primary use in clinical trials-related research. Efforts to develop more effective fMRI tasks and adapt existing study designs would help harness the advantages of fMRI and improve our ability to translate research findings into clinical trial outcomes.[vi]
PET/CT
The PET scan, mentioned above, can measure metabolic changes:
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. In clinical practice it is used to diagnose and manage cancer treatment, in cardiology and cardiac surgery, and in neurology and psychiatry.[vii]
When PET is combined with X-ray computed tomography (CT), both can be measured simultaneously, resulting in a single superimposed image. “PET–CT has revolutionized medical diagnosis in many fields, by adding precision of anatomic localization to functional imaging, which was previously lacking from pure PET imaging.[viii]
With PET-CT, MRI, and fMRI, along with all these new advances in technology, researchers are beginning to unveil the biological brain in its systemic relationship to depression and are now conducting further research to reveal the marvelous body-brain-mind connections that have been hidden since the beginning of time.
First Blood Test to Diagnose Depression
Researchers have been searching for decades for a definitive biological diagnostic test for major depression. On September 16, 2014, Northwestern University Feinberg School of Medicine reported groundbreaking news that two researchers at Northwestern had developed a blood test using RNA markers to diagnose major depression in adults.[ix] However, this test is not yet used in standard practice. Instead, tests for other bodily conditions are used to determine what is causing a person’s depression, such as a thyroid panel, complete blood count (CBC), Vitamin B12 and Folate, Vitamin D, and electrolyte and kidney/liver function tests, all of which reveal bodily causes of some forms of depression in those people with those maladies. Biomarkers in both the blood and urine can also be used in diagnosing depression.[x]
One particular study touts an instant blood test for diagnosing depression. The authors say:
Studies have demonstrated that people with depression have less ethanolamine phosphate in their blood. The DNA analysis which was done for MDD [Major depressive Disorder] has also demonstrated this. The advent of the phosphate level blood test led to the correct diagnosis of depression, 82% of the time.
However, the pathophysiology of depression indicates that this disorder affects the metabolism, the immune system and the nervous system, as well as the hypothalamus and the pituitary and the adrenal glands.[xi]
Once again, this study and blood test reveal the systemic nature of depression as it affects many bodily systems, including “metabolism, the immune system, the nervous system,” the cardiovascular system, and the various glands that produce necessary hormones.
Neurobiology of Depression
Some of the first symptoms of depression come in the form of seemingly unrelated aches and pains. “These symptoms include chronic joint pain, limb pain, back pain, gastrointestinal problems, tiredness, sleep disturbances, psychomotor activity changes, and appetite changes.” In such cases, doctors have a difficult time diagnosing depression. An article titled “The Link Between Depression and Physical Symptoms” says:
Physical pain and depression have a deeper biological connection than simple cause and effect; the transmitters that influence both pain and mood are serotonin and norepinephrine dysregulation. Dysregulation of these transmitters is linked to both depression and pain.[xii]
After relating the research that shows a deep connection between depression and physical symptoms, the article emphasizes the importance of treating the physical symptoms as well as the emotional symptoms, because if they remain, there is a higher possibility of relapsing back into the depression symptoms as well.[xiii]
Neuroimaging research also reveals structural and functional changes in the brain. Researchers have seen amygdala hyperactivity, reduced gray matter, reduced prefrontal cortex activity, and hippocampal shrinkage in depressed individuals. They are concerned about the need to find the right treatment because of such impairments as memory formation.[xiv] Dysfunction of the brain’s nerve circuit is highly involved in depression, with impaired neuroplasticity and mitochondrial shutdown. Neuroplasticity involves the formation of new neural connections, and mitochondria provide energy for cellular function.[xv] These studies underline the recognition that depression is a systemic illness, not simply wrong thinking.
Psychoneuroimmunology (PNI) Plus
In exploring the epigenesis (causes) of depression, researchers find a web of conditions acting together. They coined the word “Psychoneuroimmunology” (PNI), which refers to depression encompassing the psyche, the neurons, and the immune system. Others have observed the role of the endocrine system acting together with the neurons in depression. Another term that reveals a complex biological involvement is “Neuroendocrinology,” demonstrating the role of hormones acting together with neurons in depression. Another term combines “Psychoneuroimmunology” and “Neuroendocrinology” to form “Psychoneuroendocrineimmunology.” In an article titled “Rethinking Depression—Beyond Neurotransmitters: An Integrated Psychoneuroendocrineimmunology Frame for Depression’s Pathophysiology and Tailored Treatment,” the authors affirm that “the human being is complex and depression is a systemic and variable disorder.”[xvi]
More Yet to Be Discovered
One could go even further and add the cardiovascular system to create a new word: “Psychovascularneuroendocrineimmunology.” The word would be too long to include the gut biome with the gut-brain axis. Add to that all the bacteria and other microbes around us and within us. Thus, you have the complexity of the body and brain, as well as the environment and psychosocial interactions. And now, with the new technology and the great need to help people suffering from depression, it is no wonder that so many researchers are working to understand the systemic nature of depression and how to treat it effectively. The hope is that in the years ahead, with available and new instruments to probe the body and the brain in order to gain greater knowledge through research studies yet to be done, there will be a single drug to prescribe for each individual profile of depressed patients
Keep reading in Psychiatrists and Clinical Depression – Part 2
[i] Garry Cooper, Katy Butler, and Mary Sykes Wylie, “A Brief History of Psychotherapy,” Psychotherapy Networker, March/April, 2017, https://www.psychotherapynetworker.org/article/brief-history-psychotherapy/.
[ii] Signe Penner-Goeke and Elizabeth B. Binder, “Epigenetics and Depression,” Dialogues in Clinical Neuroscience, December 2019, https://pmc.ncbi.nlm.nih.gov/articles/PMC6952745/#sec8.
[iii] “Functional MRI (fMRI), https://my.clevelandclinic.org/health/diagnostics/25034-functional-mri-fmri.
[iv] Vasileia Kotoula, Jennifer W. Evans, Claire E Punturieri, and Carlos A. Zarate, Jr., “Review: The use of functional magnetic resonance imaging (fMRI) in clinical trials and experimental research studies for depression,” June 22, 2023, https://pmc.ncbi.nlm.nih.gov/articles/PMC10406217/#main-content.
[vii] Positron emission tomography (PET), Wikipedia, https://en.wikipedia.org/wiki/Positron_emission_tomography.
[viii] “PET/CT,” Wikipedia, 03-10-26, https://en.wikipedia.org/wiki/PET%E2%80%93CT.
[ix] Marla Paul, “First Blood Test to Diagnose Depression in adults,” https://news.feinberg.northwestern.edu/2014/09/16/redei-blood-test/.
[x] Ziqiang Lin et al, “Classifying depression using blood biomarkers: A large population study,” https://www.sciencedirect.com/science/article/abs/pii/S0022395621003460; Erin M. van Buel et al, “Major depressive disorder is associated with changes in a cluster of serum and urine biomarkers,” https://www.sciencedirect.com/science/article/abs/pii/S0022399918305725.
[xi] Rohit Kumar Verma, “An Instant Diagnosis for Depression by Blood Test,” Journal of Clinical and Diagnostic Research (JCDR), November 15, 2012, https://pmc.ncbi.nlm.nih.gov/articles/PMC3527816/
[xii] Madhukar H. Trivedi, https://pmc.ncbi.nlm.nih.gov/articles/PMC486942/#:~:text=These%20symptoms%20include%20chronic%20joint,as%20well%20as%20emotional%20symptoms.
[xiv] “Brain study shows that depression reduces size of hippocampus,” July 9, 2015, https://keck.usc.edu/news/brain-study-shows-that-depression-reduces-size-of-hippocampus/.
[xv] Ioana Rădulescu, Ana Miruna Drăgoi, Simona Corina Trifu, Mihai Bogdan Cristea, “Neuroplasticity and depression: Rewiring the brain’s networks through pharmacological therapy (Review,” August 5, 2021, https://pmc.ncbi.nlm.nih.gov/articles/PMC8383338/#:~:text=Therefore%2C%20in%20the%20case%20of,the%20stellar%20neurons%20(54).
[xvi] Anna Giulia Bottaccioli, Mauro Bologna, Francesco Bottaccioli, “Rethinking Depression—Beyond Neurotransmitters: An Integrated Psychoneuroendocrineimmunology Frame for Depression’s Pathophysiology and Tailored Treatment,” International Journal of Molecular Sciences. March 19, 2025, https://pubmed.ncbi.nlm.nih.gov/40141399/.